The Human Genome, Chapter Two

FOR IMMEDIATE RELEASE:
4/2/2002
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NIGMS Communications Office
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Many people think that scientists have--once and for all--cracked the human genetic code. Indeed, two teams of researchers published a draft sequence of our 3-billion-piece jumble of DNA "letters," chemical units called nucleotides. Yet how our bodies interpret, or "express," our cells' genetic code plays a prominent role in our everyday health. Thoroughly deciphering the code's protein-making instructions--something our bodies do with ease all the time--remains a complicated puzzle. Scientists already know that certain spelling differences in DNA cause disease. But other inheritable factors, aside from DNA, can influence how likely a person is to develop a particular disease. A compelling tale of discovery is found in researchers' quest to tease apart these so-called "epigenetic" factors that, along with diet and other environmental influences, profoundly affect our health.

The correct packaging of DNA is essential to the proper functioning of the cells that make up our bodies. Cells contain and protect their precious cargo, genes, in protein-rich complexes called chromatin. Chromatin consists of long, stringy DNA spooled around an orderly, ball-like core of proteins called histones. In a sense, chromatin acts as a gatekeeper for our genes, regulating access to DNA by cellular equipment that decodes the genetic instructions. Among other things, this arrangement permits embryos to develop the right way, and it directs precursor cells to form organs and tissues. Conversely, if access to the genes in chromatin is not stringently controlled, cancer and a variety of other diseases can be the terrible consequence.

Beads on a String

The chromatin story begins over a hundred years ago. In the late 1800s, researchers first discovered the molecules now known as histones, and there was widespread belief among scientists that these proteins--not DNA, as determined over 50 years later--were the source of heredity. In 1973, Drs. Ada and Donald Olins of the University of Tennessee, Oak Ridge and Dr. Christopher Woodcock of the University of Massachusetts, Amherst independently released preliminary reports describing electron microscopic pictures of chromatin fibers as "particles on a string." A year later, putting together the microscopy data and results from other biochemical and biophysical techniques, Dr. Roger Kornberg, then a Junior Fellow of Harvard University working at the MRC Laboratory in Cambridge, England, published a seminal paper. He proposed a model of chromatin structure as repeating units of approximately 200 nucleotide pairs of DNA and 8 histone molecules--the string and beadlike particles, respectively. Virtually every college biology student now knows this description of chromatin as "beads on a string." Beginning with these early studies, NIGMS has funded a quarter-century of groundbreaking research on chromatin--what it is, how it works, and more recently, how it is tied to cancer and other diseases.

In the mid-1960s, even though researchers did not know precisely what histones did inside cells, scientists such as Dr. Vincent Allfrey, then of the Rockefeller Institute in New York City, suspected that natural chemical tags on histones could control genes by turning them on or off. Throughout the 1970s, more scientists began to appreciate and gradually accept the connection between DNA's physical environment (chromatin) and the activity of genes. Genes are turned on (" transcribed"), for the most part, by proteins called transcriptional activators that must touch DNA to exert their effects. The basic structure of chromatin, in which DNA is spooled and compacted, would appear to be a major obstacle to the transcription process by blocking the access of activator proteins to genes. Indeed, researchers have reported many examples of how chromatin can prevent genes from being read. In the late 1980s and early 1990s, scientists such as Dr. Jerry Workman of Pennsylvania State University and Dr. Robert Kingston of Massachusetts General Hospital discovered that some transcriptional activator proteins (and often combinations of them) can attach themselves to DNA in chromatin, displacing histones. This observation proved to be a major step in researchers' understanding of how genes can be read through a veil of protective chromatin.

Another Code

Groundbreaking studies by Dr. C. David Allis of the University of Virginia Health Sciences Center have begun to reveal that a key step in how cells interpret their genetic code involves actually finding genes tucked away inside chromatin. Part of a cell's gene-decoding machinery is drawn to the histone proteins in chromatin. In recent years, Dr. Allis and other NIGMS-funded scientists have defined several cellular systems that carefully balance how histones are "marked" with a variety of natural chemical tags--called acetyl, phosphate, and methyl groups--in a specifically timed order. Putting on these tags and taking them off--something Dr. Allis refers to as the "histone code"--turns out to be a critical aspect of a cell's gene-reading activities.

The past 10 years in particular have witnessed an explosion of major discoveries by Dr. Allis and other NIGMS-funded researchers that are paving the way toward a better understanding of how genes are controlled and how certain diseases result when gene access is either too lenient or too stringent. In many cancer cells, for instance, inappropriate control of certain growth genes can fuel unchecked cell division. Scientists are finding a prevalence of telltale marks on chromatin in certain cancer cells, leaving growth genes bare and prone to near-constant activation. When histone-marking enzymes are revved up in cancer cells, these molecules become important potential targets for developing future cancer drugs.

In recent years, NIGMS-supported researchers have also made links between chromatin and normal biological processes like aging. Dr. Leonard Guarente of the Massachusetts Institute of Technology discovered that a gene-silencing protein called Sir2 removes the chromatin-marking chemical tags called acetyl groups from genes. He found that Sir2 is intimately dependent on a molecule central to the body's process of metabolizing food into energy. The finding has far-reaching implications, providing a tantalizing potential explanation for the observation by other researchers that low-calorie diets in model organisms such as yeast and worms can extend lifespan.

Writer: Alison Davis, Science Writing Contractor